The overall objective of this program is to contribute to the understanding of mechanisms controling growth and regeneration of specific neuronal connections in the CNS. These studies employ as a model system the ingrowth of sympathetic axons into the septally deafferented rat hippocampus. We will investigate two major questions:what is the nature of the stimulus eliciting sympathetic axonal reinnervation; and how is the sprouting response regulated differently in males and females? To address the first question we propose that postsynaptic inactivation is sufficient to elicit the sprouting response and we will investigate the mechanism by which muscarinic receptor blockade stimulates axonal sprouting. We will chronically treat rats with a potent and selective muscarinic antagonist, scopalomine; test a nicotinic antagonist, Alpha-bungarotoxin; combine septal lesions with a cholinergic agonist, carbachol, to attempt to block sprouting by pharmacologically activating the denervated target, and localize the denervated and reinnervated target cells using autoradiography for cholinergic and Alpha1 adrenergic receptors, respectively. To address the second question we will test two hypotheses: the growth may be regulated by circulating gonadal steroids; the septohippocampal afferent fibers or their target cells may become sexually differentiated as a result of hormone expposure during development. We will quantify observed gender differences in maturation of a population of hippocampal interneurons using cholinergic and GABAergic enzyme asays; and quantify the sprouting response in males and females gonadectomized and hormone-supplemented as adults or neonates. We will also test the generality of sexual dimorphism in axonal sprouting using 3 related systems: locus coeruleus noradrenergic sprouting in the lateral septum following fimbria lesions; septal, cholinergic sprouting and interneuronal, GABAergic sprouting in the dentate gyrus after entorhinal cortex lesions. Together these studies include pharmacological and endocrinological manipulation of neuronal growth, and neuroanatomical and biochemical analysis of post-lesion growth and normal development in the hippocampal formation of the rat. We hope that these studies will aid in identifying mechanisms conrtroling regenerative and collateral sprouting in the nervous system, and provide means of regulating, pharmacologically or hormonally, the post-lesion responses in a manner which will facilitate recovery of function after CNS damage.